The present invention relates to a novel pharmaceutical mixture comprising a profen.
In the development of pharmaceutical forms, in particular in the case of profens, the object is generally to find an optimum between 3 opposing objectives:
1. Both from the point of view of the pharmaceutical manufacturer and of the patient, it should be possible to prepare a pharmaceutical form as economically as possible. In the case of tablets, this means that with a fixed dose of active compound which is prespecified out of therapeutic necessity, the amount of the other auxiliaries which are added to the tablets should be kept as low as possible. The lower the amount of auxiliaries, the lower the production costs, which can likewise have an effect on the sale price. The production of tablets should also be as simple as possible and only comprise a few working steps in order likewise to be able to save costs in this way.
2. A tablet should optimally make available the active compound contained therein to the patient. This means an instant-release tablet should disintegrate very rapidly in the digestive fluids and rapidly release the active compound.
3. In order that it is easy to take, the tablet should have as small a form as possible (this applies particularly to high-dose active compounds). Small pharmaceutical forms are better accepted by patients and markedly increase so-called patient compliance.
It is almost impossible to fulfil these 3 requirements at the same time. When processing active compounds which are not extremely highly soluble, rapid release of an active compound from a tablet is achieved only by the addition of relatively large amounts of solubilizing auxiliaries and relatively large amounts of substances which bring about rapid disintegration and thus also rapid dissolution of the tablets. If the active compound can moreover only be tableted with difficulty, the production of a tablet is only possible using additional auxiliaries which compensate the disadvantages of the poor tabletability. Moreover, in the production of ready-to-press tableting materials, in very many cases a laborious granulation step is also necessary beforehand. It is therefore usually impossible to develop a small and economical form.
All these disadvantages are present in the case of the profens. Thus the active compound ibuprofen, for example, is administered in high doses. The dose which is usually not subject to prescription is 200 mg, and in some countries recently 400 mg. For treatment of rheumatic disorders, even pharmaceutical forms having a dose of 600 mg or 800 mg are approved by the pharmaceutical authorities in very many countries.
A further disadvantageous aspect of the profens is that they do not dissolve well. Problems can therefore occur with respect to bioavailability. Therefore for ibuprofen US Pharmacopeia USP XXIII, for example, requires a dissolution rate of at least 80% of the active compound after 60 minutes. In order to achieve a rapid dissolution rate, large amounts of the auxiliaries described above must be added to the ibuprofen in order thus to attain the required high extent of release.
Ibuprofen further shows very poor tableting behavior. The added auxiliaries must therefore at the same time also compensate for this disadvantage. A check of most ibuprofen tablets available on the market shows that the amount of active compound in the total weight of the tablets as a rule is only 55-65%.
It is further common to all these tablets that, for the preparation of the pressable tableting material, a conventional granulation or compaction must be added, since otherwise adequate solidity cannot be achieved during tableting. Granulation, however, is expensive and time-consuming.
A further criterion of the quality of profen-containing tablets is the release of the active compound in vitro. Thus according to Sucker, Fuchs and Speiser in: Pharmazeutische Technologie [Pharmaceutical Technology], Georg Thieme Verlag Stuttgart, 1978, page 283, the dissolution rate of poorly soluble substances can be increased in many cases by the addition of solubilizers. However, if it is attempted to increase the dissolution rate, for example, of ibuprofen by the addition of a solubilizer of the polyethylene glycol type, only minor success is achieved. The same applies if the stabilizer is replaced by a surfactant such as sodium dodecylsulfate.
No tablets are known on the market which contain a high amount of ibuprofen. Although a few ibuprofen-containing tablets having a high active compound content are already known from the literature, these, however, are not available on the market. Thus in EP 0 607 467 A1 pellets are described which have an active compound content of over 90% and which release the active compound (measured according to USP XXII) after 50 minutes only to 15-28%.
In EP 0 456 720 B1 granules are described which have an ibuprofen content of over 90%. The granules were prepared using PVP. Formulations containing PVP, however, exhibit considerable stability problems. Thus the release of active compound from PVP-containing granules is only 20-30% of the original value even 3 months after preparation.
In WO/8902266, a process is described in which, with the aid of an aqueous granulating process in a fluidized bed granulator, granules are prepared which can be pressed directly to give tablets without further additives, but which can only contain up to 85% of ibuprofen. The process is involved and, like all fluidized bed granulating processes, laborious and expensive. Moreover, PVP is employed for binding the granules, which leads to stability problems as mentioned above.
A. Sakr et al. [Pharm. Ind. 60, No. 3 (1998) 257-262] describe an ibuprofen tablet which contains 95% ibuprofen and was prepared by roller compaction. This process, particularly when it is carried out on the plant scale, is very laborious and poorly reproducible. Moreover, these tablets again contain the incompatible PVP. These tablets also do not meet the requirement for a rapid onset of action, as is desired in the case of a painkiller.
Moreover, it is common to all these tablets that, for the preparation of the pressable tableting material, a conventional moist granulation or compaction must again be added as already mentioned above or that PVP must be employed, which admittedly has good binding ability, but does not guarantee stability.
Surprisingly, it has now been found that a specific mixture having a high profen content can be processed very simply to give tablets which meet the highest pharmaceutical demands. In the case of an analgesic this means: small and easy-to-swallow tablets, very rapid onset of action and rapid elimination of the pain. Both are very highly desirable from the point of view of the patient.
The invention relates to a profen-containing pharmaceutical mixture, which has a profen content of over 85%, preferably over 90%, and contains up to 1% of a nonionic surfactant having an HLB of xe2x89xa79 and a customary disintegrant and also a lubricant and, if appropriate, celluloses and/or hydroxyalkylcelluloses.
HLB is understood as meaning the xe2x80x9chydrophilic-lipophilic balancexe2x80x9d, cf. Sucker, Fuchs and Speiser in: Pharmazeutische Technologie [Pharmaceutical Technology], Georg Thieme Verlag Stuttgart, 1978, page 305. The HLB in the mixture according to the invention is xe2x89xa79, preferably xe2x89xa711 and in particular xe2x89xa712.
The details in percent (%) relate to percentage by weight everywhere in the application.
The designation xe2x80x9cprofenxe2x80x9d means antiinflammatory substances containing the structural element 
wherein the dotted lines are free bonds.
Examples of such compounds are preferably ibuprofen and its optically active S form. Further suitable profens are flunoxa-profen, flurbiprofen, ibufenac, ibuproxam, ketoprofen and loxo-rofen. The compounds can optionally be present in the form of their physiologically tolerable salts. These are to be understood as meaning the alkali metal and alkaline earth metal salts and also salts with amino acids such as lysine. Preferred are the sodium salts and the salts with lysine.
The term xe2x80x9cpharmaceutical mixturexe2x80x9d particularly includes administration forms such as tablets, film-coated tablets, sugar-coated tablets and also the mixtures and pellets which are filled into the hard gelatin capsules.
The high active compound content of profen in the administration form is achieved by incorporating into the administration form an amount of up to 1%, preferably 0.01-0.8%, (based on the amount of profen in the administration form) of a nonionic surfactant. Larger amounts of surfactant do not produce any further advantages.
Suitable nonionic surfactants having an HLB of 9 and over are, for example, sucrose esters; partial fatty acid esters of polyhydroxyethylenesorbitan, such as polyethylene glycol(20) sorbitan monolaurate, monopalmitate, monostearate and monooleate; poly-ethylene glycol(20) sorbitan tristearate and trioleate (which are available, for example, under the trade name Tween(copyright); polyethylene glycol(4) sorbitan monolaurate and monostearate; polyethylene glycol(5) sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl stearyl ether (which are obtainable, for example, under the trade name Cremophor(copyright) O; corresponding lauryl ethers (which are obtainable, for example, under the trade names Brij(copyright) 30 and Brij(copyright) 35); polyhydroxyethylene fatty acid esters (which are obtainable, for example, under the trademarks Myrj(copyright) 45, Myrj(copyright) 52 and Myrj(copyright) 59); ethylene oxide/propylene oxide block copolymers (which are obtainable, for example, under the trade names Pluronic(copyright) and Lutrol(copyright); furthermore sugar ethers and sugar esters; phospholipids and their derivatives; and ethoxylated triglycerides such as the derivatives of castor oil (which are available, for example, under the trade names Cremophor(copyright) EL, Cremophor(copyright) RH, Cremophor(copyright) RH 40, Cremophor(copyright) RH 60). Among these, Cremophor(copyright) RH 40 and Cremophor(copyright) 60 are particularly suitable. The surfactants available under the designation Tween(copyright) likewise behave very favorably. Very particular mention is to be made of Tween(copyright) 80. The use of mixtures of these surfactants is likewise advantageous.
Customary disintegrants are, for example, sodium carboxymethyl starch and sodium carboxymethylcellulose. Coarse-grain celluloses have the same properties.
The amount of disintegrant in the pharmaceutical form is normally in the range from 1 to 4%.
Suitable lubricants are, for example, magnesium stearate and calcium stearate, stearic acid, stearic acid derivatives (which are available, for example, under the trade names Precirol(copyright), talc, Aerosil(copyright), polyethylene glycols (mainly types having a molecular weight of 4000 and higher) and hydrogenated cottonseed and castor oils.
The amount of lubricant in the pharmaceutical form is normally in the range from 0.1 to 0.7%.
The addition of celluloses or hydroxyalkylcelluloses to the pharmaceutical form is not absolutely necessary, but the addition of a small amount of such a substance proves advantageous. The addition of hydroxyalkylcelluloses, in particular of hydroxymethylpropylcellulose 3 cp, hydroxymethylpropylcellulose 6 cp or hydroxypropylcellulose such as, for example, Klucel(copyright) EF, is preferred.
The amount of celluloses and hydroxyalkylcelluloses in the pharmaceutical form is normally in the range from 1 to 4%.
Although further pharmaceutical auxiliaries can be added to the pharmaceutical forms, they are not necessary for their production.
The mean particle size of the profen used does not play any great part in the preparation of the administration forms, as a rule it is 10-100 xcexcm, preferably 20-80 xcexcm.
The novel mixture is especially suitable for the production of solid pharmaceutical forms such as granules in hard gelatin capsules or tablets which contain the profen in an amount from 85-98%, preferably 90-98%, of their total weight.
The expression xe2x80x9cpharmaceutical formxe2x80x9d should distinguish not only the so-called xe2x80x9cfinished pharmaceutical formxe2x80x9d, but also tablets without a coating or, in the case of multilayer tablets, the layer containing the profen or the granules containing the profen, which can be shaped to give pellets.
Tablet coatings are not considered in the calculation of the % content of the pharmaceutical form. If the tablets are press-coated or multilayer tablets, the % details for the profen and the auxiliaries thus relate only to the portions or layers of the pharmaceutical form which contain the profen.
For the preparation of, for example, tablets, the surfactants are preferably mixed in dry form with the profen, that is in the case of a liquid surfactant the addition and dispersion of the surfactant is carried out without further addition of a diluent and in the case of a solid surfactant in some cases without prior micronization.
The surfactants, however, can also be dissolved in water or organic solvents and evenly distributed on the profen. However, the moist mixture then still has to be dried. The amount of water or solvent used here is 3-10% (based on the total amount), clearly below the amount of liquid which is needed for granulation (for example 35-40% based on the total amount).
After addition of the customary auxiliaries, the mixture thus obtained can be compressed directly, that is without granulation, to give tablets.
It was extremely surprising that as a result of the addition of the surfactants mentioned, which, for example, in the case of the polyoxyethylene sorbitan esters are usually highly viscous liquids having a honey-like consistency, profens such as ibuprofen can be processed simply to give tablets having very high pharmaceutical demands. It contradicts all previous experiences that as the result of the addition of a surfactant to a poorly tabletable active compound such as ibuprofen a good compressibility can be achieved. The previous experiences assume that compressibility more likely decreases as a result of the addition of surfactants. Moreover, it was completely surprising that the mixtures thus obtained have a flowability which also cannot nearly be achieved by the sole addition of magnesium stearate and Aerosil(copyright).
Moreover, it is very surprising that the novel tablets even have a very high hardness when they are pressed using an only relatively low compression force.
The following Examples illustrate the invention.
All measurements of active compound releases were carried out according to USP XXIII. A paddle apparatus was used and operated at 50 rpm at pH 7.2.